The goal of this Phase 1 SBIR proposal is to determine whether the melatonin analog PD6735 (6-chloro- (R) B-methyl melatonin) is neuroprotective in a rat traumatic brain injury (TBI) model. A critical and largely unmet need exists for effective TBI neuroprotectant drugs. Free radicals and neuroinflammatory components mediate brain cortical tissue damage resulting in significant neurologic deficits after TBI. Preliminary Studies suggest that PD6735, like its structural parent melatonin, is an effective neuroprotectant in a rat TBI model. In these studies brain cortical tissue damage was assessed by quantitative morphometry in PD6735-treated TBI rats. PD6735 reduced cortical tissue damage by 68 % compared to vehicle in TBI animals (P= 0.01). In an in vitro assay of brain injury, PD6735 was three- to six-fold superior in inhibiting free radical and neuroinflammatory mediator production compared to melatonin suggesting a possible mechanism of the PD6735-induced neuroprotection observed in vivo. A total of ten Phase 1 and Phase 2 clinical studies demonstrate that PD6735 is safe and well tolerated in humans in doses up to 100 mq and lacks any adverse side effects compared to placebo. In contrast, melatonin produces significant clinically adverse events in humans at doses greater than 1 mg. PD6735's neuroprotective properties in vivo and in vitro combined with its safety and tolerance in humans at high doses form the underlying rationale for the proposed rat TBI drug efficacy study. We hypothesize that PD6735 will exhibit robust neuroprotective efficacy by reducing cortical tissue damage and neurologic deficits in TBI rats. Given PD6735's safety and tolerability in humans, positive results in the proposed rat TBI study will allow rapid initiation of PD6735 clinical studies in TBI patients. Our Specific Aim is: Specific Aim: Determine PD6735's neuroprotective effect on spatial learning and memory employing the Morris water maze and brain cortical tissue damage employing quantitative morphometry in TBI rats. The three controls included will be sham TBI rats, vehicle-, and melatonin-(as structural control) treated TBI rats. [unreadable] [unreadable]